Provided byUCLDiscovery CORE This article isprotected rights by All copyright. reserved. 10.111 doi: lead todifferences version between this andthe ofPleasecite article Version Record. this as been and throughtypesetting, proofreadingwhich may thecopyediting, process, pagination This article has accepted been Running Title: intramural , small vessel , periarterial drainage Keywords: Southampton,Email: Hampshire, 6YD,SO16 UK. Southampton SouthGeneral AcademicBlock, Road, Hospital, MP806, Tremona Roxana Carare,Prof O Medicine, UniversitySouthampton,Faculty of of aut Corresponding study *Contributed equally the to 3 UK. London, ofNeurology NeurologyInstitute Hospitalthe and National for Neurosurgery, and 2 1 Ajay Verma Matthew Sharp MacGregor r anatomyfine The perivascular compartmentthe human the in brain: of Articletype : Scientific Correspondence MR MATTHEW MACGREGORSHARP (Orcid ID : 0000

elevance to dilated perivascular todilated elevance spaces in cerebral amyloidangiopathy Research Centre, Department Stroke ResearchDepartment Centre, Repairof Rehabilitation,UCL Brain and Medicine, Faculty Southampton, of University of AcceptedUSA. Biogen, Article 1/nan.12480

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1 for publication and undergone and buthasfor not review publication full peer , Diederik, Bulters 2* , Roxana O Carare O Roxana ,

spaces, cerebral amyloid angiopathy, white angiopathy, amyloid cerebral spaces,

- 0002 1 , Sebastian Brandner, - Southampton,UK; 6623 1* [email protected]

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Metadata, citationandsimilarpapersatcore.ac.uk

2 , Janice Holton ,

2 , This article isprotected rights by All copyright. reserved. Accepted( limitans glia the to adjacent layer leptomeningeal the b) and parenchyma the a) between formed compartment lepto perivascular distinct a have may brains young in matter white the in arterioles that suggests This [5]. cells leptomeningeal of layers incomplete have venules whereas matter, white the in layer incomplete wi often matter, white and grey both in leptomeninges of layer complete one by enveloped are arterioles that dog elderly an in demonstrated we Recently [4]. solutes and ISF of drainage of failure indicate may and matter white the in dilate conditions, pathological in even cortex, cerebral the in around PVS detectable no are There 3]. [2, (CAA) angiopathy amyloid cerebral or MRI poten can and membranes basement arterial along solutes and ISF of (IPAD) drainage periarterial intramural the to related are they because dynamics (ISF) fluid interstitial of study the for interest particular of are (PVS) spaces ageing normal to Wallerian compared present, of are markers Articledegeneration where (AD) disease Alzheimer’s in signatures distinct molecular have WMH that demonstrated was it recently though breakdown, barrier or disease vessel small with t assumed been patients has It . in finding imaging brain frequent most the are (CT), scanning tomographic computed on attenuation low or (MRI), imaging Cerebral imagingresonance scanning Aβ Abbreviations: ofList , amyloid - eiga lyr daet o h sd o tnc mda aig ie the side facing media tunica of side the to adjacent layer meningeal AD with patients of matter white the in described been have PVS dilated visible , ht mte hprneste (M) bevd n antc resonance magnetic on observed (WMH) hyperintensities matter white IPAD , intramural periarterial drainage , CAA , PVS ,

cerebral cerebral angiopathyamyloid , perivascular spaces hat WMH are due to or blood or arteriosclerosis to due are WMH hat , WMH , ISF

, , , CT interstitial fluid white matter hyperintensities , computed tomographic

tially be detected by MRI. by detected be tially 1. iae perivascular Dilated [1].

hra PS can PVS whereas , MRI th a second a th , magnetic - brain .

This article isprotected rights by All copyright. reserved. white the in arteries revealed TEM by cavernoma the from distant most Acceptedmargin p the at matter white subcortical of Analysis observed. abnormality other no with gliosis, reactive of evidence showed region subcortical REC white the from approval ethical samples cortical the that reported Hospital General Southampton under in neuropathology consent patient after obtained was Tissue cavernoma. underlying an to due seizures for lobectomy frontal removal vignette blend, image with layout auto to set script photomerge automated an with CS6 Photoshop Adobe using montage a as reconstructed then and acquired M was System, arteries/case) Imaging n=3 (from walls arterial of Soft images power high of series A platform, Germany). Imaging TEM Universal iTEM software, (formerly software capture image EMSIS and camera digital III MegaView EMSIS a operating microscope electron T12 Technai FEI a using viewed and grids 80 ultrathin Article and trimmed were blocks Tissue [6]. TEM for processed and sections cube 1mm into cut buffer, PIPES 0.1M in glutaraldehyde 3% plus formaldehyde 3.4% in overnight fixed protoc standard our following performed exact the (TEM) microscopy mechanisms. IPAD clarify further to PVS electron dilated the of location anatomical transmission by identify we dementia, w patient a of matter suitable studies.for thewhitemammals, ultrastructural biopsytissue from using Here post fixed of lack the been has generally, more and CAA of limitation One PVS. dilated a of formation the allow to expanded be could potentially that feet) end oto tsu ws band rm 26 a from obtained was tissue Control and geometric Correction. Distortion - nm sections cut. The ultrathin The cut. sections nm

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This article isprotected rights by All copyright. reserved. Accepted G). visiblefragments 1 (Figure pial the to adjacentobserved wasmater pia layer of (Figure F).One parenchyma 1 surrounding pial intact an had PVS The PVS. TEM vasculitis. of evidence arterie revealed no was There parenchyma. neural the Histological in plaques TEM. and histology diagnostic mature and diffuse frequent and CAA severe showed assessment for divided was specimen lobe of causes treatable for non a investigation underwent he dementia, his of part occlusive As E). active 1 an (Figure suggesting vasculopathy region, occipital left the in lesion hyperintense Diffusion siderosis. cortical widespread and superficial microbleeds cerebral lobar strictly multiple showed D) susceptibility and C) 1 (Figure echo gradient Article several over dementia, progressive 68 a from obtained was tissue CAA were side the mater either of glial observed pial basement membranes (Figure B). 1 pia the and muscle smooth the basement of glial membranes basement the between pial observed spaces no were the There membrane. from and by endothelium separated the were from cells membranes muscle basement smooth of Layers observed. was membrane intact an and junctions tight with cells endothelial of layer complete A A). 1(Figure membranes basement their and cells of layers apposed closely with matter - glial baseme glial s in the white matter with thick and distorted walls, with an enlarged an with walls, distorted and thick with matter white the in s nt membrane. This layer appeared highly disrupted with only only with disrupted highly appeared layer This membrane. nt

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This article isprotected rights by All copyright. reserved. Accepted authorsthis confirm interest. that hasThe contentarticle no conflicts of Conflict of Interest againstimmunization A efficiently drain to unable is matter white the from fluid that such arteries, cortical the in compromised become pathways IPAD the which by mechanism a propose we observations our on Based resection. wide the from a with t taken was patient care although lesion, vascular a from MRI was tissue control as the Furthermore, accumulate WMH. to to contributing fluid for substrate anatomical pial the to adjacent mater pia membrane basement the destroyed have may CAA and Articleageing age not is patient CAA The together. compressed all are leptomeninges of layer one and membrane basement muscle, of layers as brain normal the in arteries cortical around PVS no is there that confirmed we study present the In [8]. cortex cerebral the from space subarachnoid the thusseparating space, subarachnoid the in vessels the to on brain the of surface reflected is mater pia the cortex, cerebral the of surface the enter arteries cortical As [8]. particles be of injection can intracerebral parenchyma, the brain by experimentally the expanded and wall an of aspect outer the between The [7]. ganglia basal the of matter grey the in and the Dilatation of PVS occurs in the white matter of the cerebral hemispheres, in hemispheres, cerebral the of matter white the in occurs PVS of Dilatation

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This article isprotected rights by All copyright. reserved. neurosurgery, psychiatry.and 2013;84(6):624 MRI study.haemorrhage:a intracerebral multicentre Journal cohort ,of al. Enlarged et perivascular spacesas a underlyingmarker of in arteriopathy 2. 2017;134(3):459neuropathologica. neurodegenerativenotwith pathology,but small Acta vessel disease. white Parietal lesions Alzheimer's in matter disease associated are with cortical 1. References theinterpretationcontributed to ofdata and writing manuscript. the authors All histopathology. the performed JH and SB tissue. control the provided DB MM study. the designed DJW and AV ROC, Author Contributions: was aftertissue consent obtained patient ethical approvalunder Control patient). (CAA 14/SC/0098 number approval ethical UK) (BRAIN Network th from obtained with tissue study wasThe conducted Approval: Ethical fundedand by Biogen. approval Network number14/SC/0098. workThis (BRAINUK)ethical was supported study The with was tissue obtained conducted Brainthe from UK Archive Information Acknowledgments:

Accepted Article Charidimou A,Charidimou MeegahageFox R, Z, Moya KE, Graham S, McAleese L, ELJ Walker

- 73.

Peeters Peeters Vandermeeren Y,Laloux A, P, - - S per S 9.

formed the electron microscopy. electron the formed , Johnson M, Erskine al.Johnson , M,Erskine D, et e UK Brain Archive Brain Information UK e REC 12/NW/0794.

This article isprotected rights by All copyright. reserved. 2013;1(1):48. communications. immunotherapy implications for Alzheimer's in Acta neuro disease. complexImmune impairs solutes formation elimination the of the brain: from 10. 43. ofcerebralpresence amyloid angiopathy.Acta ne isimpairedPerivascular solutes drainage inof theageing mouse brainand in the 9. 3):337 ganglia ofthebasal human their brain: relati 8. 305. tumefactiveNeuroradiol. J spaces. Giant 2005;26(2):298 AJNR Am perivascular 7. NY:2017. p. Springer NewYork; 367 Clausen BE, Laman JD,Inflammation: editors. Methods and Protocols. New York, Cerebral of MembranesAssessment Basement Microscopy. Using Electron In: 6. (Lond).Clin 2017;131(22):2737Sci structure ofthe perivascular The the oldin compartmentcanine casebrain: study.a 5. As Three DementiaSunnybrook Alzheimer's DiseaseStudy, Neuroimagingand Initiative, I. inNeuroimaging hyperintensitymatter elderly burden The studies: White cohort 4. independently burden.Brain. of amyloid 2017;140(4):1107 is visible location with associated disease perivascular Alzheimer's space 3.

Accepted Article2016;12(2):203 sociation.

- - CityAlzheimer's & Study. dementia the journalof : the Alzheimer's Carare RO, RO, Carare Teeling JL,NicollHawkes RO, Puntener CA, et U, al. JA, Weller Hawkes Hartig NicollJA, RO, CA, SchliebsR, Kacza J, etal. Weller W, Hutchings H, ZhangPollock RO, M, the PerivascularET. spacesin Weller Osborn KL, Salzman AG, MM,Page A,Sharp Morris Sharp MM, CriswellFinucane H, RO, Dobson TP, Verma et C, A, al. Weller MasellisRamirez McNeelyScott CJ, J, SE AA, M,Black Banerjee 46.

G,Fox Kim HJ, Jager HR,Charidimou D, Z, A, et MRI al. Wilson

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House P, Jinkins HouseJR, P, A, Cooper et Ditchfield al. JA,

A, Weller RO,Carare Quantitative A, RO. Weller - 44. - 75.

onship toonship lacunes.Anat. J 1997;191 (Pt uropathologica. 2011;121(4):431

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, Alzheimer's , Disease pathologica - - - This article isprotected rights by All copyright. reserved. Accepted smooth muscle space perivascular dilated a by surrounded in seen box the by highlighted wall vessel mater The patient. CAA a membrane basement glial pial the of expansion and arrows) (white of matter Article white subcortical endothelium frontal right the from artery region occipital left the in lesion hyperintense siderosis superficial cortical widespread (arrows)and microbleeds cerebral strictlylobar multiple revealed dilated areventricles The dementia. progressing space. perivascular dilated no with in seen box the by highlighted wall vessel (pgbm) cells endothelium The patient. control a of matter white subcortical 1: Figure Legends Figure (sm) (pm)

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This article isprotected rights by All copyright. reserved. Accepted Article